It is widely asserted that imipramine (IMI) and the other tricyclic antidepressants do not exert a significant antidepressant effect for 1-3 weeks, although some authors state that this effect may be seen within a few days. This question, of evident practical importance, is also of considerable theoretical interest because of recent reports that tricyclic drugs, including IMI and its metabolite desipramine (DMI), have a variety of chronic pharmacological actions which may counteract their acute effect of blocking amine reuptake. clearly, the mechanism of action of the tricyclic drugs cannot be fully understood without an accurate understanding of the time course of their clinical effects. The proposed research studies should provide this information. The primary objectives in this research are: 1) to develop a simple test for predicting the daily dosage of IMI that a patient will require to achieve optimal plasma concentrations of IMI and DMI at steady-state; and 2) to determine how much time elapses before the pharmacological action(s) of IMI begin to produce a significant therapeutic effect in optimally-treated depressed outpatients. Studies 1 and 2 will be concerned with developing the predictive test, the use of which should make it possible rapidly and safely to raise patients' plasma IMI and DMI concentrations to optimal therapeutic levels. Study 3 will be a double-blind, placebo-controlled investigation of the rapidity of clinical antidepressant response to imipramine. It is anticipated that this research will further our understanding of how tricyclic antidepressants work and that it may suggest ways in which the drugs can be used more effectively in the treatment of depression.